AGA Clinical Practice Guideline on Endoscopic Eradication Therapy of Barrett's Esophagus and Related Neoplasia.

BACKGROUND & AIMS: Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). Endoscopic eradication therapy (EET) can be effective in eradicating BE and related neoplasia and has greater risk of harms and resource use than surveillance endoscopy. This clinical practice guideline aims to inform clinicians and patients by providing evidence-based practice recommendations for the use of EET in BE and related neoplasia. METHODS: The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients, conducted an evidence review, and used the Evidence-to-Decision Framework to develop recommendations regarding the use of EET in patients with BE under the following scenarios: presence of (1) high-grade dysplasia, (2) low-grade dysplasia, (3) no dysplasia, and (4) choice of stepwise endoscopic mucosal resection (EMR) or focal EMR plus ablation, and (5) endoscopic submucosal dissection vs EMR. Clinical recommendations were based on the balance between desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 5 recommendations for the use of EET in BE and related neoplasia. Based on the available evidence, the panel made a strong recommendation in favor of EET in patients with BE high-grade dysplasia and conditional recommendation against EET in BE without dysplasia. The panel made a conditional recommendation in favor of EET in BE low-grade dysplasia; patients with BE low-grade dysplasia who place a higher value on the potential harms and lower value on the benefits (which are uncertain) regarding reduction of esophageal cancer mortality could reasonably select surveillance endoscopy. In patients with visible lesions, a conditional recommendation was made in favor of focal EMR plus ablation over stepwise EMR. In patients with visible neoplastic lesions undergoing resection, the use of either endoscopic mucosal resection or endoscopic submucosal dissection was suggested based on lesion characteristics. CONCLUSIONS: This document provides a comprehensive outline of the indications for EET in the management of BE and related neoplasia. Guidance is also provided regarding the considerations surrounding implementation of EET. Providers should engage in shared decision making based on patient preferences. Limitations and gaps in the evidence are highlighted to guide future research opportunities.

Reduced risk of de novo Barrett esophagus after bariatric surgery: a national database study.

BACKGROUND: Bariatric surgery is an effective treatment for obesity and may decrease the morbidity and mortality of obesity-associated cancers. OBJECTIVE: We investigated the risk of a new diagnosis of Barrett esophagus (BE) following bariatric surgery compared to screening colonoscopy controls. SETTING: Large national database including patients who received care in inpatient, outpatient, and specialty care services. METHODS: A national healthcare database (TriNetX, LLC) was used for this analysis. Cases included adults (aged ≥18 yr) who had undergone either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Controls included adults undergoing screening colonoscopy and an esophagoduodenoscopy on the same day and had never undergone bariatric surgery. Cases and controls were propensity-matched for confounders. The risk of de novo diagnosis of BE at least 1 year after bariatric surgery was compared between cases and controls. Secondary analyses examined the effect of bariatric surgery on metabolic outcomes such as weight loss and body mass index (BMI). The risk of de novo diagnosis of BE in SG was compared with RYGB. Odds ratios (OR) and 95% CI were used to report on these associations. RESULTS: In the propensity-matched analysis, patients who had undergone a bariatric surgical procedure showed a significantly reduced risk of de novo BE when compared with screening colonoscopy controls (.67 [.48, .94]). There was substantial reduction in weight and BMI in the bariatric surgery group when compared with baseline. There was no significant difference in de novo BE diagnosis between the propensity-matched SG and RYGB groups (.77 [.5, 1.2]). CONCLUSION: Patients who underwent bariatric surgery (RYGB or SG) had a lower risk of being diagnosed with BE compared with screening colonoscopy controls who did not receive bariatric surgery. This effect appears to be largely mediated by reduction in weight and BMI.

Prevalence and Predictors of Barrett's Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases.

BACKGROUND & AIMS: Guidelines suggest a single screening esophagogastroduodenoscopy (EGD) in patients with multiple risk factors for Barrett's esophagus (BE). We aimed to determine BE prevalence and predictors on repeat EGD after a negative initial EGD, using 2 large national databases (GI Quality Improvement Consortium [GIQuIC] and TriNetX). METHODS: Patients who underwent at least 2 EGDs were included and those with BE or esophageal adenocarcinoma detected at initial EGD were excluded. Patient demographics and prevalence of BE on repeat EGD were collected. Multivariate logistic regression was performed to assess for independent risk factors for BE detected on the repeat EGD. RESULTS: In 214,318 and 153,445 patients undergoing at least 2 EGDs over a median follow-up of 28-35 months, the prevalence of BE on repeat EGD was 1.7% in GIQuIC and 3.4% in TriNetX, respectively (26%-45% of baseline BE prevalence). Most (89%) patients had nondysplastic BE. The prevalence of BE remained stable over time (from 1 to >5 years from negative initial EGD) but increased with increasing number of risk factors. BE prevalence in a high-risk population (gastroesophageal reflux disease plus ≥1 risk factor for BE) was 3%-4%. CONCLUSIONS: In this study of >350,000 patients, rates of BE on repeat EGD ranged from 1.7%-3.4%, and were higher in those with multiple risk factors. Most were likely missed at initial evaluation, underscoring the importance of a high-quality initial endoscopic examination. Although routine repeat endoscopic BE screening after a negative initial examination is not recommended, repeat screening may be considered in carefully selected patients with gastroesophageal reflux disease and ≥2 risk factors for BE, potentially using nonendoscopic tools.

Patients With Esophageal Adenocarcinoma With Prior Gastroesophageal Reflux Disease Symptoms Are Similar to Those Without Gastroesophageal Reflux Disease: A Cross-Sectional Study.

INTRODUCTION: A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. METHODS: In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. RESULTS: Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC-related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. DISCUSSION: Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Sex differences in esophageal cancer overall and by histological subtype.

Esophageal cancer is the seventh most common type of cancer in the world, the sixth leading cause of cancer-related death and its incidence is expected to rise 140% in the world in a period of 10 years until 2025. The overall incidence is higher in males, while data about prognosis and survival are not well established yet. The goal of this study was to carry out a comprehensive analysis of differences between sexes and other covariates in patients diagnosed with primary esophageal cancer. Data from 2005 to 2020 were obtained from the University Hospitals (UH) Seidman Cancer Center and from 2005 to 2018 from SEER. Patients were categorized according to histological subtype and divided according to sex. Pearson Chi-square test was used to compare variables of interest by sex and the influence of sex on survival was assessed by Kaplan Meier, log rank tests and Cox proportional hazards regression models. A total of 1205 patients were used for analysis. Sex differences in all types were found for age at diagnosis, histology, smoking status and prescriptions of NSAIDs and in SCC for age at diagnosis and alcoholism. Survival analysis didn't showed differences between males and females on univariable and multivariable models. Males have a higher incidence of Esophageal Cancer and its two main subtypes but none of the comprehensive set of variables analyzed showed to be strongly or unique correlated with this sex difference in incidence nor are they associated with a sex difference in survival.

Prediction of Progression in Barrett's Esophagus Using a Tissue Systems Pathology Test: A Pooled Analysis of International Multicenter Studies.

BACKGROUND & AIMS: Prediction of progression risk in Barrett's esophagus (BE) may enable personalized management. We aimed to assess the adjunct value of a tissue systems pathology test (TissueCypher) performed on paraffin-embedded biopsy tissue, when added to expert pathology review in predicting incident progression, pooling individual patient-level data from multiple international studies METHODS: Demographics, clinical features, the TissueCypher risk class/score, and progression status were analyzed. Conditional logistical regression analysis was used to develop multivariable models predicting incident progression with and without the TissueCypher risk class (low, intermediate, high). Concordance (c-) statistics were calculated and compared with likelihood ratio tests to assess predictive ability of models. A risk prediction calculator integrating clinical variables and TissueCypher risk class was also developed. RESULTS: Data from 552 patients with baseline no (n = 472), indefinite (n = 32), or low-grade dysplasia (n = 48) (comprising 152 incident progressors and 400 non-progressors) were analyzed. A high-risk test class independently predicted increased risk of progression to high-grade dysplasia/adenocarcinoma (odds ratio, 6.0; 95% confidence interval, 2.9-12.0), along with expert confirmed low-grade dysplasia (odds ratio, 2.9; 95% confidence interval, 1.2-7.2). Model prediction of progression with the TissueCypher risk class incorporated was significantly superior than without, in the whole cohort (c-statistic 0.75 vs 0.68; P < .0001) and the nondysplastic BE subset (c-statistic 0.72 vs 0.63; P < .0001). Sensitivity and specificity of the high risk TissueCypher class were 38% and 94%, respectively. CONCLUSIONS: An objective tissue systems pathology test high-risk class is a strong independent predictor of incident progression in patients with BE, substantially improving progression risk prediction over clinical variables alone. Although test specificity was high, sensitivity was modest.

Age of diagnosis in familial Barrett's associated neoplasia.

The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett's Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial-a single affected family member, duplex-two affected family members, and multiplex-three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett's associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members.

A survey of physician training and credentialing in endoscopic submucosal dissection in the United States.

BACKGROUND: Endoscopic submucosal dissection (ESD) is technically challenging, has a longer learning curve and a greater complication rate than most new endoscopic procedures. Formal training and credentialing guidelines for ESD are currently lacking in the United States (US). AIM: To survey ESD experts across the US to determine their learning process and obtain their opinion on how training and credentialing for ESD should develop. DESIGN: Anonymous electronic survey. SUBJECTS: ASGE members who are practicing US endoscopists. METHODS: The survey was developed by iterative revisions of questions administered to three investigators who have been performing ESD for > 5 years. The final survey was distributed electronically to US endoscopists who had previously attended ESD expert conferences. RESULTS: Thirty-five (58.3%) of 60 practicing ESD experts responded to the survey. A majority (91%) were in university-based, community, or tertiary care hospitals. All practitioners practiced on porcine explants and observed live ESD procedures as part of the training. Out of the participants, 75.8% received formal supervised hands-on training on porcine explants and/or humans before performing ESD independently. Fifty percent indicated that their facility had written guidelines specifically for ESD credentialing. Four out of 5 felt that credentialing requirements should include attending weekend ESD courses, observing live procedures, practicing on explants, and advanced endoscopic training in interventional endoscopy such as an additional year of fellowship. LIMITATIONS: Survey completion rate of 58.3%. CONCLUSION: ESD training should include practicing on explants, observation of live procedures, training in interventional endoscopy, and attending educational courses. Credentialing guidelines for ESD based on expert opinion need to be developed in the US.

Wide-area transepithelial sampling for dysplasia detection in Barrett's esophagus: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Seattle protocol forceps biopsy sampling (FB) is currently recommended for surveillance in Barrett's esophagus (BE) but limited by sampling error and lack of compliance. Wide-area transepithelial sampling with 3-dimensional analysis (WATS3D; CDx Diagnostics, Suffern, NY, USA) is reported to increase BE dysplasia detection. We assessed the incremental yield and clinical significance of WATS3D for dysplasia detection over FB in a systematic review and meta-analysis. METHODS: We queried major scientific databases for studies using WATS3D and FB from 2000 to 2020. The primary outcome was the incremental yield of WATS3D-detected dysplasia (defined as a composite of indefinite for dysplasia, low- and high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) over FB. Secondary outcomes were incremental yields of HGD/EAC and rate of reconfirmation of WATS3D dysplasia on subsequent FB. RESULTS: Meta-analysis of 7 eligible studies demonstrated that FB diagnosed dysplasia in 15.9% of cases, whereas the incremental yield with WATS3D was 7.2% (95% confidence interval, 3.9%-11.5%; I2= 92.1%). Meta-analysis of 6 studies demonstrated that FB diagnosed HGD/EAC in 2.3% of patients, whereas the incremental yield with WATS3D was 2.1% (95% confidence interval, .4%-5.3%; I2= 92.7%). Notably, WATS3D was negative in 62.5% of cases where FB identified dysplasia. Two studies reported reconfirmation of WATS3D dysplasia with FB histology in only 20 patients. CONCLUSIONS: WATS3D increases dysplasia detection; however, the clinical significance of this increased dysplasia detection remains uncertain. Data from endoscopic follow-up to ascertain FB histology in patients with dysplasia based solely on WATS3D are needed to determine the optimal clinical application and significance of WATS3D-only dysplasia.

Novel Screening Alternatives for Barrett Esophagus.

Barrett esophagus (BE) is the only known premalignant precursor to esophageal adenocarcinoma (EAC), a deadly malignancy that carries a dismal prognosis. Guidelines currently recommend screening for BE only in high-risk populations, such as patients with chronic gastroesophageal reflux disease (GERD) and 1 or more additional risk factors. A GERD-centered approach to BE screening likely leads to a large number of missed EAC cases, as the true population prevalence of BE is thought to be much higher than current estimates. Mass screening for BE has been proposed but is fraught with challenges. Esophagogastroduodenoscopy screening is the current gold standard for BE detection, but it is expensive and cumbersome and carries a small potential for unwanted harms. Transnasal endoscopy is simple, cost-effective, and well tolerated, but it has not found widespread acceptance among physicians and patients. Esophageal capsule endoscopy, despite being well tolerated and accepted, has not been shown to be cost-effective. Newer minimally invasive, nonendoscopic techniques for BE screening have shown promise in prospective clinical trials. Pragmatic head-to-head trials comparing these techniques will help determine the path forward and could herald a new future for population-based BE screening.

Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-ß and JNK Signaling Pathways in Esophageal Cancer.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression. METHODS: We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice. RESULTS: Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-ß (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells. CONCLUSIONS: In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.

Subtypes of Barrett's oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis.

OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE). DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies. RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment. CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

The Effect of Endoscopic Surveillance in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Guidelines recommend endoscopic surveillance of patients with Barrett's esophagus (BE) to identify those with dysplasia (a precursor of carcinoma) or early-stage esophageal adenocarcinoma (EAC) who can be treated endoscopically. However, it is unclear whether surveillance increases survival times of patients with BE. We performed a systematic review and meta-analysis to qualitatively and quantitatively examine evidence for the association of endoscopic surveillance in patients with BE with survival and other outcomes. METHODS: We searched publication databases for studies reporting the effects of endoscopic surveillance on mortality and other EAC-related outcomes. We reviewed randomized controlled trials, case-control studies, studies comparing patients with BE who received regular surveillance with those who did not receive regular surveillance, and studies comparing outcomes of patients with surveillance-detected EAC vs symptom-detected EACs. We performed a meta-analysis of surveillance studies to generate summary estimates using a random effects model. The primary aim was to examine the association of BE surveillance on EAC-related mortality. Secondary aims were to examine the association of BE surveillance with all-cause mortality and EAC stage at time of diagnosis. RESULTS: A single case-control study did not show any association between surveillance and EAC-related mortality. A meta-analysis of 4 cohort studies found that lower EAC-related and all-cause mortality were associated with regular surveillance (relative risk, 0.60; 95% CI, 0.50-0.71; hazard ratio, 0.75; 95% CI, 0.59-0.94). Meta-analysis of 12 cohort studies showed lower EAC-related and all-cause mortality among patients with surveillance-detected EAC vs symptom-detected EAC (relative risk, 0.73; 95% CI, 0.57-0.94; hazard ratio, 0.59; 95% CI, 0.45-0.76). Lead- and length-time bias adjustment substantially attenuated/eliminated the observed benefits. Surveillance was associated with detection of EAC at earlier stages. A randomized trial is underway to evaluate the effects of endoscopic surveillance on mortality in patients with BE. CONCLUSIONS: In a systematic review and meta-analysis of the effects of surveillance in patients with BE, surveillance as currently performed was associated with detection of earlier-stage EAC and may provide a small survival benefit. However, the effects of confounding biases on these estimates are not fully defined and may completely or partially explain the observed differences between surveyed and unsurveyed patients.

Effects of Weight-Loss Medications on Cardiometabolic Risk Profiles: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: We performed a systematic review and network meta-analysis to evaluate the overall and comparative effects of weight-loss medications approved by the Food and Drug Administration for long-term use on cardiometabolic risk profiles of obese adults. METHODS: We performed a systematic literature review through February 28, 2017 to identify randomized clinical trials of the effects of Food and Drug Administration-approved weight-loss medications (ie, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide) administered to obese adults for 1 year or more, compared with placebo or another active agent. Outcomes of interest included changes in blood glucose (fasting blood glucose [FBG] and hemoglobin A1c), cholesterol profile (low-density lipoprotein and high-density lipoproteins), blood pressure (BP; systolic/diastolic), and waist circumference (WC). We performed pair-wise and network meta-analyses with outcomes reported as weighted and standardized mean differences. Quality of evidence was rated using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: In a meta-analysis of 28 randomized controlled trials (29,018 participants; median body mass index, 36.1 kg/m2), we associated weight-loss medications with a modest decrease in FBG (weighted mean difference, 4.0 mg/dL; 95% confidence interval, -4.4 to -3.6 mg/dL) and WC (weighted mean difference, reduction of 3.3 cm; 95% confidence interval, -3.5 to -3.1 cm), without clinically meaningful changes in systolic/diastolic BP or cholesterol profile vs placebo (standardized mean difference <0.2); effects varied among drugs. Phentermine-topiramate use was associated with a substantial decrease in WC and a modest decrease in FBG, hemoglobin A1c, and BP, and had minimal effect on cholesterol. Liraglutide use was associated with a substantial decrease in FBG, hemoglobin A1c, and WC, and a minimal effect on BP and cholesterol. Naltrexone-bupropion use was associated with moderate increase in high-density lipoprotein cholesterol, but had a minimal effect on FBG and WC. Orlistat use was associated with a decrease in low-density lipoprotein and high-density lipoprotein cholesterol. No drug improved all cardiometabolic risk factors. CONCLUSIONS: In a systematic review and network meta-analysis, we found Food and Drug Administration-approved weight-loss medications to have only modest positive effects on cardiometabolic risk profile. Further research is needed to evaluate the long-term cardiometabolic benefits of these medications. PROSPERO: CRD42016039486.

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus.

We report a biomarker-based non-endoscopic method for detecting Barrett's esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.

Diagnosis and treatment of irritable bowel syndrome with predominant constipation in the primary-care setting: focus on linaclotide.

Irritable bowel syndrome (IBS) is a complex functional gastrointestinal disorder that is exceedingly common in clinical practice. IBS with predominant constipation (IBS-C) is a subtype of IBS that accounts for more than a third of the IBS diagnosed. Diagnosis of IBS requires a careful personalized approach, a comprehensive clinical history, limited but relevant investigations, and continued follow-up. Major IBS societies and guidelines recommend offering a positive diagnosis of IBS based on presenting symptomatology. Abdominal pain that may or may not be relieved by defecation is the cardinal symptom of IBS; distension and bloating are other common symptoms. Careful attention should be paid to alarm symptoms before a diagnosis of IBS is made. Pharmacotherapy with linaclotide is recommended for moderate-severe IBS-C, based on high-quality evidence from randomized controlled trials. Diarrhea is the major side effect of linaclotide, and limited cost-effectiveness data currently exist.

Genomic regions associated with susceptibility to Barrett's esophagus and esophageal adenocarcinoma in African Americans: The cross BETRNet admixture study.

BACKGROUND: Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are far more prevalent in European Americans than in African Americans. Hypothesizing that this racial disparity in prevalence might represent a genetic susceptibility, we used an admixture mapping approach to interrogate disease association with genomic differences between European and African ancestry. METHODS: Formalin fixed paraffin embedded samples were identified from 54 African Americans with BE or EAC through review of surgical pathology databases at participating Barrett's Esophagus Translational Research Network (BETRNet) institutions. DNA was extracted from normal tissue, and genotyped on the Illumina OmniQuad SNP chip. Case-only admixture mapping analysis was performed on the data from both all 54 cases and also on a subset of 28 cases with high genotyping quality. Haplotype phases were inferred with Beagle 3.3.2, and local African and European ancestries were inferred with SABER plus. Disease association was tested by estimating and testing excess European ancestry and contrasting it to excess African ancestry. RESULTS: Both datasets, the 54 cases and the 28 cases, identified two admixture regions. An association of excess European ancestry on chromosome 11p reached a 5% genome-wide significance threshold, corresponding to -log10(P) = 4.28. A second peak on chromosome 8q reached -log10(P) = 2.73. The converse analysis examining excess African ancestry found no genetic regions with significant excess African ancestry associated with BE and EAC. On average, the regions on chromosomes 8q and 11p showed excess European ancestry of 15% and 20%, respectively. CONCLUSIONS: Chromosomal regions on 11p15 and 8q22-24 are associated with excess European ancestry in African Americans with BE and EAC. Because GWAS have not reported any variants in these two regions, low frequency and/or rare disease associated variants that confer susceptibility to developing BE and EAC may be driving the observed European ancestry association evidence.